Compositions and methods for treating inflammatory conditions of the bowel

a technology of inflammatory conditions and compositions, applied in the field of compositions and methods for treating inflammatory conditions, can solve the problems of poor success, little or no selectivity, and the immunologic aspects of the pathogenesis of ibd cannot answer the basic question, so as to prevent intestinal fibrosis and delay the progression of signs

Active Publication Date: 2010-02-11
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]The present invention also provides a method of treatment, comprising, providing a subject at risk for inflammatory bowel disease and a composition comprising an AT1a antagonist or derivative thereof, and administering to the subject a therapeutically effective amount of the composition so as to prevent the subject from experiencing signs or symptoms of inflammatory bowel disease, related inflammatory conditions of the gastrointestinal tracts, or other gastrointestinal disorders. In some embodiments, the administration of the therapeutic composition comprising an AT1a antagonist or derivative thereof delays the progression of the signs or symptoms of inflammatory bowel disease. In one embodiment, the subject at risk for inflammatory bowel disease is a human. In a preferred embodiment, the human is selected from a young adult, a person living in the United States, a person living in England, a person living in Northern Europe, a person of Jewish descent, a person living in a developing nation, a person with family members who suffer from inflammatory bowel disease or a person determined to carry an in

Problems solved by technology

However, even the latest developments in the immunologic aspects of the pathogenesis of IBD cannot answer the basic question, i.e., whether the detected changes in humoral and cellular immunity reflect a pri

Method used

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  • Compositions and methods for treating inflammatory conditions of the bowel
  • Compositions and methods for treating inflammatory conditions of the bowel
  • Compositions and methods for treating inflammatory conditions of the bowel

Examples

Experimental program
Comparison scheme
Effect test

example 1

Design and characterization of AT1a Antagonists

[0166]Analogs that are closely related structurally to losartan (See, e.g., compound 1 in FIG. 2) and candesartan (See, e.g., FIG. 3, below) are provided. Each analog has structural attributes that render the molecules highly impermeable to cell membranes (both epithelial cells and adjacent vasculature). This limits the analogs' exposure in vivo to the intestine alone.

[0167]AT1a antagonists: Analogs 2, 3 and 4 are based on losartan 1 (See FIG. 2). Losartan analog 2 lacks the chloro group on the imidazole molecule and has hydrogen in its place. Losartan analog 3 lacks the chloro group on the imidazole molecule, and possesses a carboxylic acid instead of the hydroxylmethyl group. These changes are designed to yield very low intestinal absorption. Compound 5, similar to 2, lacks the chloro group on the imidazole molecule, and the hydroxymethyl group has been replaced by a carboxylic acid. Compounds 6 and 7, are similar to compounds 3 and 4...

example 2

Synthetic Strategy

[0170]A variety of synthetic routes utilized to generate analogs and / or derivatives are shown in FIGS. 5-7. For example synthesis schemes for losartan analogs and / or derivatives are shown in FIG. 5. The losartan analogue 2 is prepared from readily available losartan 1 in a single step by catalytic hydrogenolysis of the chloro group (See FIG. 5). In some embodiments, the analog 2 is readily oxidized to the novel carboxylic acid 5 with a manganese-based oxidizing agent. Compounds 3 and 4 (Shown in FIG. 6) are prepared starting with commercially available 2-butyl-4-hydroxymethyl-5-chloroimidazole 9. Diacids 6 and 7 are then obtained by simple saponification of the corresponding esters 4 and 3, respectively. Compound 8 is prepared by the route shown in FIG. 7, starting with compound 10 prepared in FIG. 4. The present invention can utilize a number of analytical methods (e.g., including, but not limited to, NMR, MS, HPLC and combustion analyses) to characterize the puri...

example 3

Screening and characterization of AT1a Antagonists

Materials and Methods

[0171]Animals. Specific pathogen-free male, 8-week old C57BL / 6 mice (Taconic Farms Inc, Germantown, N.Y.) were maintained in a 12-h night rhythm at 23° C. and a relative humidity of 40-60%. Animals were fed standard rodent chow (LabDiet 5001Rodent Diet, PMI Nutrition International, LLC, Brentwood, Mo.) ad libitum. All experiments were approved by the University Committee on Use and Care of Animals at the University of Michigan.

[0172]In vitro assessment of AT1aR antagonism. The present invention provides high throughput screening methods to detect AT1a antagonism in an in vitro setting. A variation of an in vitro model established by McAllister-Lucas et al. (See, e.g., McAllister-Lucas et al., PNAS, 2007; 104:139-44) was used to measure the degree of antagonism on AT1a receptor signaling. This model makes use of the fact that Ang II-dependent stimulation of the AT1a receptor results in rapid activation of the NF-κ...

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Abstract

The present invention provides compositions and methods for treating inflammatory conditions (e.g., of the bowel). In particular, the present invention provides methods of treating (e.g., therapeutically and/or prophylactically treating) inflammatory conditions (e.g., of the bowel), compositions useful for such methods (e.g., antagonists and/or inhibitors of angiotensin II (AngII) receptor Type 1a (AT1a)), and methods of identifying, characterizing and/or optimizing such compositions. Compositions and methods of the present invention find use in, among other things, clinical (e.g. therapeutic and preventative medicine) and research applications.

Description

[0001]This application claims priority to U.S. Provisional Patent Application Ser. Nos. 61 / 086,393 filed 5 Aug. 2008 and 61 / 177,054 filed 11 May 2008, each of which is hereby incorporated by reference in its entirety.[0002]This invention was made with government support under AI44076-09 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention provides compositions and methods for treating inflammatory conditions (e.g., of the bowel). In particular, the present invention provides methods of treating (e.g., therapeutically and / or prophylactically treating) inflammatory conditions (e.g., of the bowel), compositions useful for such methods (e.g., antagonists and / or inhibitors of angiotensin II (AngII) receptor Type 1a (AT1a)), and methods of identifying, characterizing and / or optimizing such compositions. Compositions and methods of the present invention find use in, among other things, clinical (e...

Claims

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Application Information

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IPC IPC(8): A61K31/56C12Q1/02
CPCA61K31/56G01N2500/02G01N33/566
Inventor TEITELBAUM, DANIEL H.SHOWALTER, HOLLISLARSEN, SCOTTLUCAS, PETERKOGA, HIROYUKI
Owner RGT UNIV OF MICHIGAN
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